Arsenic (As) contamination through drinking water causes skin, lung and bladder cancers. However, the mechanism by which As causes cancers has not been elucidated. The long-term goal of this study is to determine the mechanism of As carcinogenesis and identify molecular targets for the treatment and prevention of cancers resulting from As exposure. Accumulating evidence suggests a critical role of microRNAs (miRNAs) in cancer progression. Nevertheless, it has not been determined whether miRNAs causally contribute to chemical carcinogenesis. Our preliminary studies demonstrated that As treatment caused depletion of miR-200b and 200c and induced transformation of human normal bronchial epithelial cells in which p53 expression was knocked down. Re- expressing miR-200b or 200c significantly and greatly reversed transformed phenotypes. We hypothesize that loss of p53 and down-regulation of miR-200b and/or 200c contribute to arsenic lung carcinogenesis. Three specific aims are proposed to test this hypothesis. Specific Aim 1: To determine the roles of miR-200b/200c and their target genes ZEB1 and ZEB2 in As-induced cell transformation and tumorigenesis. We hypothesize that ectopic expression of miR-200b/200c or depletion of ZEB1/ZEB2 inhibits cell transformation by As. Specific Aim 2: To investigate whether whether the ZEB1/ZEB2 heterozygous knockout mice are resistant or less sensitive to As lung carcinogenesis. We hypothesize that ZEB1/ZEB2 heterozygous knockout mice will be resistant or less sensitive to As lung carcinogenesis. Specific Aim 3: To determine the mechanism by which As causes ZEB1 and ZEB2 expression. Based on our preliminary findings, we hypothesize that TGF-beta signaling plays a critical role in the induction of ZEB1/ZEB2 expression by As exposure. We will investigate the role of Smad-mediated and non-Smad TGF-beta signaling in As-induced expression of ZEB1 and ZEB2. PUBLIC HEALTH RELEVANCE: Arsenic (As) is one of the most common environmental pollutants and exposure to As through drinking water is a major environmental health concern, affectsing millions of people in the United States and many other countries. The goal of this study is to determine the mechanism by which As exposure causes cancers and identify molecular targets for the treatment and prevention of cancers resulting from As exposure.